Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

New imine-phosphine palladium complexes [Pd(P-N)(CH 3 )(CH 3 CN)](BF 4 ) (P-N ) o-(diphenylphosphino)-N-benzaldimine derivatives) are synthesized and are found to be active for copolymerization of COethylene and CO-norbornylene, respectively. Stepwise addition of carbon monoxide and various olefins into the new complexes is investigated.

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

A robust, cost effective and high yielding manufacturing process for enantiomerically enriched (S)-allylic amine 3, a key intermediate for fully synthetic tetracyclines have been developed.Two novel and scalable asymmetric vinylations resulting in high to excellent stereoselectivity have been developed for the key step. The final product is purified by an efficient crystallization of a L-tartaric salt. The process described has been used to manufacture ~350 kg of the tartaric salt of 3 with 99.0% ee in 8 steps (35% overall yield) from cheap and readily available dimethyl maleate.

A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified, and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo.